Muscle is divided into three types: skeletal, cardiac, and smooth. Briefly, smooth muscle is found in all muscles where contraction is involuntary, except for heart muscle. Generally, smooth muscle is composed of elongated, spindle-shaped, nucleated cells arranged parallel to one another and to the long axis of the muscle.
Smooth muscle is classified both functionally, and anatomically. When classified functionally, it is broken into two groups: multi-unit, and single-unit smooth muscle. Briefly, multi-unit smooth muscle is activated by nerves which cause contraction of independent muscle units, and thus is not spontaneously active. Examples of multi-unit muscle may be found in large arteries and veins, the urinary bladder, and the iris and ciliary muscles of the eye. In contrast to multi-unit smooth muscle, single-unit smooth muscle is usually spontaneously active, and contains tight junctions which facilitate the contraction of the muscle as a single unit. Examples of single-unit smooth muscle may be found in the vasculature (small veins, small arteries, and arterioles), the bile duct, and the walls of the gastrointestinal and urinogenital systems (gut, ureter, and uterus).
When smooth muscle is anatomically classified, it is generally divided into two groups: vascular and non-vascular. Briefly, vascular smooth muscle consists only of blood vessels (arteries, arterioles, and veins), whereas non-vascular muscle includes all other types of smooth muscle (e.g., gastrointestinal (stomach, duodenum, ileum, jejunum, caecum, and colon), spleen, trachea/bronchus, seminal vesicle, ductus deferens, corpus cavernosum, biliary tract, ureter, and uterus).
Many diseases are characterized by the inability of smooth muscle to relax. For example, hypertension is a disease found in 15%-20% of all adults in the United States. This condition is characterized by persistently high arterial blood pressure which, if left untreated, may lead to other serious cardiovascular diseases such as heart failure, ischemia, renal failure, and stroke. Hypertension is one of the most important public health problems facing developed countries.
Because of the health risk associated with untreated hypertension, the importance of treating those who suffer from elevated blood pressure has been recognized. Clinical trials have shown that appropriate pharmacological treatment of patients with moderate or severe hypertension reduces the risk of stroke, renal failure, and congestive heart failure. Based upon these studies, patients are now commonly treated with antihypertensive drags in order to lower diastolic blood pressure ("DBP") to levels below 90 mmHg. Common drugs which are used for this purpose include diuretics (hydrochlorothiazide, chlorthalidone), sympatholytics (clonidine, atenolol, prazosin), vasodilators (minoxidil, sodium nitroprusside), angiotensin converting enzyme inhibitors (captopril, enalapril), and calcium entry blockers (nifedipine, nitrendipine). The selection of a specific drug depends upon the severity of the disease, the patient's age and lifestyle, side effects, cost, and concomitant diseases and therapies.
One approach to the treatment of hypertension is to effect the reduction of elevated blood pressure through blood vessel dilation, which results in an increase of blood vessel diameter and concomitant blood pressure reduction. One class of compounds which are commonly utilized to dilate blood vessels are nitrovasodilators, which have been utilized for the relief of anginal attacks and the treatment of hypertension. Clinically useful nitrovasodilators include organic nitrites and nitrates such as amyl nitrite, glyceryl trinitrate (nitroglycerin), isosorbide dinitrate, erythrityl tetranitrate, and pentaerythritol as well as an inorganic nitric oxide donor, sodium nitroprusside.
Nitroglycerin and sodium nitroprusside are the most commonly used nitrovasodilators. Nitroglycerin is therapeutically useful for the treatment of angina pectoris and gastrointestinal spasm, while sodium nitroprusside is primarily utilized for the treatment of hypertensive emergencies. Nitroglycerin may either be administered at the time of anginal attack or prophylactically in anticipation of exercise or stress. Although nitroglycerin is effective in relief of acute attack, continual exposure to nitroglycerin and other organic nitrates results in a reduction in the ability of these compounds to vasodilate blood vessels. Because of the tolerance that develops from their chronic use, these nitrovasodilators have limited applicability.
Sodium nitroprusside is likewise effective in lowering blood pressure, although its use is primarily limited to hypertensive emergencies due to its efficacy and toxicity. In particular, the infusion of sodium nitroprusside at high doses or for long periods of time (over 24 hours) is associated with the toxicities resulting from the accumulation of cyanide and or thiocyanate.
Accordingly, there is a need in the art for physiologically acceptable smooth muscle relaxants which do not result in the development of tolerance and do not have toxic side effects. The present invention fulfills these needs, and further, provides other, related advantages.